A team of scientists at Aarhus University in Denmark reported a remarkable discovery in this month’s issue of the journal Genes & Development. Genetic regulation is a complex and intricate affair carefully orchestrated by an array of proteins and other factors. While the basics are well understood, the researchers discovered that the length of the gene itself may also have a role, adding another twist to the already complex and intricate story of genetic regulation.

A gene is often thought of as a stretch of DNA which encodes RNA which is in turn translated into a protein molecule. A gene isn’t simply a stretch of DNA, though. The DNA that makes up a gene is richly endowed with features that control when and how it becomes translated into RNA and what happens to that RNA molecule afterwards. The promoter region at the start of the gene regulates its expression; promoters have various short stretches of DNA, like TGTCTC or TATAAA, which are recognized by the molecular machinery that reads DNA. There’s also a terminator region at the end which marks where transcription into RNA should stop. The transcribed RNA molecule then gets processed in various ways before it leaves the nucleus for the ribosomes, molecular complexes which read RNA and assemble a protein accordingly.

Having already shown that terminators can also affect gene expression, Pia Andersen, Søren Lykke-Andersen and Torben Heick Jensen did an elegant series of experiments to understand how this happens. In addition to marking the end of transcription, terminators contain different signals which help guide RNA processing. One of these is the polyA signal, which gets recognized by proteins that cut off the end of the RNA molecule and replace it with a special sequence called a polyA tail. The polyA tail helps the RNA get out of the nucleus and protects it from being broken down in the rest of the cell, as well as being important for translation of the RNA into a protein.

To investigate the role of the polyA signal, the researchers constructed an artificial gene with a promoter and a polyA-signal-containing terminator separated by a fragment of a yeast gene. They introduced this construct into human cell cultures and determined how strongly it was expressed by measuring the amount of the corresponding RNA. When a short fragment (around 400 bases) was used to separate the promoter and terminator, the gene was barely expressed at all, but adding as little as 280 bases to the fragment was enough to fully restore the gene to full activity. In other words, short genes get switched off because a terminator with a polyA signal is too close to the promoter. The researchers think this may be because the molecular machinery recruited by the terminator interferes with the promoter or perhaps even because of a physical interaction between the promoter and terminator themselves.

Of course, short genes exist in every genome, including our own. How do these genes get expressed? Some short genes are read by different proteins, but others use a terminator that doesn’t contain a polyA signal, thereby avoiding problematic interactions. To demonstrate this, the team repeated the experiment with a terminator from one of these short genes instead of the polyA-terminator and found that even the short constructs were fully expressed. Out of the 59 known human genes that produce an RNA molecule less than 500 bases long, the researchers found only two with a polyA signal in the terminator; by contrast, genes between 500 and 3000 bases in length had the signal 56% of the time.

Living creatures need to exquisitely control the expression of genes in both space and time in order to develop correctly and respond appropriately to changes in the environment. A lot of our understanding of this process has been based on functional units of DNA that activate or repress genes by acting as binding sites for proteins and protein complexes. The effect of spatial and structural factors is much less clear, since these interactions have been more challenging to understand and manipulate. This is a really great paper which adds to our growing understanding of how the shape and structure of DNA can regulate gene expression. Like everything else in biology, the regulation of genes is complex, multi-layered and often self-referential….which is part of what makes it so beautiful.